Protein kinases are a series of structurally related enzymes that are responsible for the control of signal transduction processes within the cell. They exert their physiological functions through catalyzing the phosphorylation of proteins (or substrates) and thereby modulating the cellular activity of the substrates, including modulating various important biological processes, such as cell growth, survival and differentiation, organ formation and morphogenesis, neovascularization, tissue repair and regeneration. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events.
JAK is a non-receptor type tyrosine kinase, and belongs to the family of protein kinases. The molecular weight of JAK is about 120 kDa to 140 kDa. In mammals, there are four members in the JAK family: JAK1 (also known as Janus kinase-1), JAK2 (also known as Janus kinase-2), JAK3 (also known as Janus kinase-3) and TYK2 (also known as protein-tyrosine kinase 2). These kinases exert their functions through interaction of cytokines and cytokine receptors (see Rodig S., et al., “Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses”, Cell, 1998, 93 (3), 373-83).
JAK plays a key role in the signal transduction of cytokines. The downstream substrates of the JAK family of kinases include the signal transducer and activator of transcription (STAT) proteins. Many diseases are associated with abnormal JAK/STAT signal transduction, such as immune system diseases (e.g., organ transplant rejection), autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type-I diabetes, lupus, psoriasis), allergic conditions (e.g., asthma, food allergy, atopic dermatitis and rhinitis), skin diseases (e.g., psoriasis, atopic dermatitis, rash), solid and hematologic malignancies (e.g., prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, leukemia, lymphoma, multiple myeloma), and myeloproliferative disorders (including erythrocytosis, idiopathic thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome or systematic mast cell disease.
Blocking signal transduction at the level of the JAK kinases is believed to hold promises for developing new treatments for JAK-related diseases such as inflammatory diseases, autoimmune diseases, myeloproliferative disorders and cancers, to name a few. JAK inhibition is also anticipated to have therapeutic benefits in patients with skin immune disorders (such as psoriasis and skin sensitization). Therefore, it is desired to develop novel JAK inhibitors, so as to more effectively treat JAK-related diseases.
For example, the expression levels of interleukin IL-6, IL-15, interferon (IFN), granulocyte-macrophage colony stimulating factor (GM-CSF) and the like are significantly elevated in the rheumatoid arthritis synovial tissue, which plays a crucial role in the occurrence and development of disorders. All the above-mentioned cytokines exert their functions via the JAK-STAT signaling pathway. Therefore, targeted blocking of the JAK-STAT pathway can achieve the purpose of improving the pathophysiological process of rheumatoid arthritis (see Joel M. K. et al., Arthritis Rheum. 2009, 60, 1859-1905).
For JAK inhibitors, some studies have been performed (see, e.g., Peter Norman, “Selective JAK inhibitors in development for rheumatoid arthritis”, Expert Opin. Investig. Drugs, 2014, 23 (8), 1067-77). Among them, Baricitinib is a drug candidate for the treatment of rheumatoid arthritis, and multiple Phase III clinical studies are ongoing in the United States (see CN102026999). Tofacitinib is currently the only JAK1 and JAK3 selective inhibitor approved by FDA in the United States for the treatment of rheumatoid arthritis (see Kremer, J., et al., “The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690, 550 versus placebo”, Arthritis & Rheumatism, 2009, 60 (7), 1895-1905). However, several adverse effects are reported for patients taking Tofacitinib, such as potential serious infections, and the increased risk of cancer and heart failure (Tofacitinib is labeled with a black box warning of serious infections and cancer risks by FDA regulation). These adverse reactions may be due to its inhibition of the JAK3 enzyme. In addition, Tofacitinib has a short half-life in human, and thus twice daily administration is required. Moreover, Tofacitinib cannot be co-administered with a disease modifying anti-rheumatic drug (DMARD) (e.g., methotrexate). Therefore, it is desired to develop JAK inhibitors having improved JAK selectivity and pharmacokinetic properties and being able to be co-administered with a DMARD (e.g., methotrexate), so as to provide patients with better therapeutic effects and reduced adverse reactions.